Vitamin D & Breast Cancer: New Research & Recommendations JoEllen Welsh, PhD Empire Innovations Professor University at Albany Cancer Research Center
Vitamin D Biology Pre-D3 7-dehydrocholesterol UV Cholecalciferol DIET Ergocalciferol Vitamin D Pool D3 Metabolism 25-hydroxy vitamin D Metabolism 1,25-dihydroxy vitamin D 25D Vitamin D Receptor 1,25D
The Vitamin D Receptor: Triggers vitamin D actions in body Vit D VDR Regulates thousands of genes Bone & Muscle Metabolism Ca & P Cell Growth and Function Immune System Cardiovascular
Studies on Vitamin D & Breast Cancer Diet, supplements Sun, season, geography Blood levels: 25D VDR function Biomarkers Pre-neoplastic lesions Cancer incidence Disease free survival Cancer mortality Treatment side effects
Sunlight Exposure & Breast Cancer UV Exposure Index Breast Cancer Relative Risk 1 (low) 1.0 2 0.8 3 0.6 4 (high) 0.5 p value <0.01
Blood levels of Vitamin D & Breast Cancer Meta Analysis: Serum 25D & Breast Cancer Risk Breast Cancer Risk 5 Case Control Studies >3000 cases + >3600 controls rr Relative Risk = 1 OVERALL (0.598, P<.001) Yin et al, Eur J Cancer 46:2196, 2010 Higher Vitamin D Status = Lower Risk of Breast Cancer
JCO August 10, 2009 vol. 27 no. 23 3757-3763 Vitamin D & Breast Cancer Survival Serum 25D & Breast Cancer Mortality Serum 25D & Disease-Free Survival Freedman et al, J Nat Cancer Inst, 2007 Goodwin et al, J Clin Oncol, 2009 Higher Vitamin D Status = Lower Death Rate from Breast Cancer
Does Vitamin D Supplementation Reduce Cancer Development? Randomized, placebo-controlled trial 1,179 post-menopausal women 1400mg Ca + 1100 IU vitamin D daily Caveats: small study few cancer cases Lappe et al, ACJN 85:1586, 2007
The Women s Health Initiative Study Randomized, placebo-controlled trial >30,000 post-menopausal women 1000mg Ca + 400 IU vitamin D daily Total Cancer Invasive Breast Cancer Initial results: no effects of CaD on fractures, cardiovascular disease, cancer or mortality Caveats: Low dose of vit D Poor compliance Wide use of vit D supplements Colorectal Cancer Re-analysis: include only women who were NOT taking CaD at randomization Bolland et al, AJCN 2011
What biological mechanisms link vitamin D and breast cancer?
The Cancer Development Process Environmental carcinogen Activation Active carcinogen Inflammation and Growth Promoters Internal stresses Normal Cell Damaged Cell Early Stage Cancer Late Stage Cancer Normal years Cancer
Possible mechanisms for Vitamin D Prevention of Cancer Vitamin D Normal Cells Prevents excess growth? Protects against gene mutations? Neutralizes toxins? Inhibits inflammation?
Vitamin D pathway in human breast cells VDR Normal breast cells accumulate 25D from blood Metabolize 25D to 1,25D 1,25D binds VDR and induces cell quiescence
Mice without VDR have abnormal Mammary Glands during development and aging Normal and VDR Knockout mice WT Puberty Pregnancy VDR KO Aging WT VDR KO
Mice without VDR have increased rate of mammary carcinogenesis in situ cancer Breast Tumor Incidence Normal VDR KO Presence of VDR in normal breast tissue prevents cancer development
Does vitamin D have any effects on breast cancer cells? Human Tumors: 80% VDR positive Not correlated with estrogen or progesterone receptor Amount decreases as cancer progresses VDR negative tumors appear to be more aggressive Established cancer cell lines express VDR VDR in human breast tissue and tumors
1,25D Induces Growth Arrest & Cell Death in Breast Cancer Cells in vitro 1,25D Control + 1,25D p21, p27 cyclin D1/cdk 4 cyclin A/cdk2 c-myc Dephosphorylation Rb Cell, nuclear condensation Bcl-2/Bax ratio cytochrome c release ROS generation Protease activity G 0 /G 1, S phase DNA fragmentation MCF-7 human breast cancer cells Growth Arrest Apoptosis & Autophagy Caveat: Need high doses of 1,25D to trigger effects
Human breast cancers respond to high doses of active Vitamin D Treatment Gene Chip 1 2 3 4 5 Patient # Doses are higher than natural levels found in the body
Topical vitamin D is effective for skin disorders Systemic doses have toxicity Not yet Can Vitamin D be used to treat breast cancer?
Super-Potent Vitamin D-like Drugs would be needed for treating Advanced Cancers Vitamin D Vitamin D Drugs 1,25D EB1089
Synthetic Vitamin D Drugs Stop Growth of Experimental Breast Tumors Tumor Growth Rate Tumor Size * * Demonstrates that super potent vitamin D-like drugs can inhibit growth of human breast tumors
Summary, Part 1 Vitamin D actions on Breast Cells Normal human mammary cells: Express VDR and vitamin D activating enzymes Internalize 25D from blood and convert it to 1,25D Are growth inhibited by physiological concentrations of 25D 1,25D & VDR trigger many mechanisms that suppress tumor development Cancer cells/tumors: Less VDR than normal cells Less sensitive to natural levels of vitamin D in the body Cancer cells respond only to high doses of active form: 1,25D
Recap. Low body stores of vitamin D may increase risk for cancer development High vitamin D status may improve outcome But cancers may become resistant to vitamin D Synthetic forms of vitamin D may prove useful for cancer treatment Vitamin D is present in low amounts in food Healthy persons can produce vitamin D in the skin but only upon exposure to sunlight
Part 2: Vitamin D Status and Recommendations
Many people do not have ideal vitamin D status World wide: 30-50% of healthy children and adults Higher in persons with highly pigmented skin WHY?
Where we live matters.. From Nov- April, sunlight is NOT strong enough for vitamin D production Diet and Supplements are Essential!!
Guidelines for Vitamin D intake Age Group Upper RDA Limit Food Amt IU Vit D
UV Production vs Oral Supplementation 15 mins = 10,000 IU!!! MED = minimal erythema dose: minimum amount of UVB that produces redness 24 hrs after exposure
What are blood levels of vitamin D in people with high sun exposure? Serum 25-Vitamin D 200 150 100 50 0 Lifeguards Preferred range 0 2000 4000 6000 8000 RDA 600 IU?? Maasai Vitamin D IU/day
What about toxicity of vitamin D? nm 2500 250 25 Oral Toxicity associated with 25D > 250nM Requires chronic oral doses >10,000 IU/day No toxicity from UV generated vitamin D
Revised Criteria for Vitamin D Status Deficient <30nM Insufficient 30-50nM Preferred Range 50-100 nm Toxic >250nM Rickets, Osteomalacia Chronic Disease Healthy Calcemic overload Serum 25D
Take Home Messages Vitamin D acts as a tumor suppressor in mammary gland Growth inhibition/ induction of differentiation Prevention of DNA damage Regulation of inflammation Vitamin D insufficiency is common Serum 25D should be maintained ~100 nm Not easy from diet alone
Acknowledgements Glendon Zinser Matthew Rowling Meggan Keith Carly Kemmis Judy Narvaez Don Matthews Erika LaPorta Kate Simmons Sarah Beaudin Jean Han Cintia Milani Martin Tenniswood Sridhar Chittur Marie Demay Rene St-Arnaud Shigeaki Kato Robert Weinberg Martin Hewison Maria Folgueira Tim Sellati Nick Mantis Funded by NIH, DOD BCRP, Komen Fdn & A Sister s Hope